Malaria is transmitted by Anopheles mosquitoes and has a devastating impact on human health and the socioeconomic conditions in endemic regions. The transmission of vector-borne pathogens is influenced by the vector s innate immune system which is largely regulated at the transcriptional and post-transcriptional level. The long-term goal of the PIs research is to elucidate, at the molecular level, the biological processes that take place between the Anopheles mosquito, its innate immune system and the malaria parasite, for the development of novel malaria control strategies. Our published and preliminary studies have shown that the mosquito IMD pathway - controlled innate immune response fulfills required criteria for an anti-Plasmodium effector system that could be used for the development of a malaria control strategy based on genetically modified Plasmodium-resistant mosquitoes. While micro RNAs have proven to play essential roles in regulating a variety of processes including immune response, their role in modulating mosquito resistance to human malaria parasite infection has not yet been explored. One miRNA can control the expression of a variety of genes, including those encoding immune response-regulators and effectors that block Plasmodium infection of the mosquito. We have identified several miRNAs that are predicted to target multiple transcripts encoding IMD pathway -factors and -regulated effectors. We have also shown that silencing of such miRNAs render mosquitoes more resistant to P. falciparum infection. This proposal seeks to characterize the implication of A. gambiae miRNAs in regulating anti-P. falciparum defense and asses their effectiveness for the development malaria control strategies based on genetically modified mosquitoes, using novel innovative miRNA sponge methodology.